In tissue, for reaction using energy, for example, biosynthesis, active biological transport, muscle contraction etc., the energy is supplied by hydrolysis of adenosine triphosphate (ATP). ATP is produced by oxidation of metabolic fuel which yields much energy, such as glucose and free fatty acids. In oxidative tissues such as muscle, ATP is mostly produced from acetyl-CoA that enters citric acid cycle. Acetyl-CoA is produced by oxidation of glucose via glycolytic pathway or β oxidation of free fatty acid. An enzyme that plays a pivotal role in controlling acetyl-CoA production from glucose is PDH. PDH catalyses the oxidation of pyruvate to acetyl-CoA and carbon dioxide with concomitant reduction of nicotinamide adenine dinucleotide (NAD) to NADH.
PDH is a multienzyme complex consisting of three enzyme components (E1, E2 and E3) and some subunits localized in mitochondria matrix. E1, E2 and E3 are responsible for decarboxylation from pyruvate, production of acetyl-CoA and reduction of NAD to NADH, respectively. Two classes of enzyme having regulatory function are associated with the complex. One is PDHK, which are protein kinases having specificity to PDH. The role thereof is to inactivate E1α subunit of the complex by phosphorylation. The other is PDH phosphatases, which are specific protein phosphatases which activate PDH via dephosphorylation of E1α subunit. The proportion of PDH in its active (dephosphorylated) state is determined by the balance of kinase activity and phosphatase activity. The kinase activity is regulated by relative concentrations of metabolic substrates. For example, the kinase activity is activated by an increase in the NADH/NAD, acetyl-CoA/CoA or ATP/adenosine diphosphate (ADP) ratios, and inhibited by pyruvate.
Four PDHK isoenzymes have been identified in mammalian tissues. Particularly, PDHK2 is expressed in a wide range of tissues including the liver, skeletal muscles and adipose tissues involved in glucose metabolism. Since it shows comparatively high sensitivity to activation by increased NADH/NAD or acetyl-CoA/CoA and inhibition by pyruvate, involvement in a short-term regulation of glucose metabolism is suggested.
In diseases such as insulin-dependent (type 1) diabetes and non-insulin-dependent (type 2) diabetes and the like, oxidation of lipids is increased with a concomitant reduction in utilization of glucose. This is one of the factors causing hyperglycemia. When the oxidative glucose metabolism is reduced in type 1 and type 2 diabetes and obesity, PDH activity is also reduced. It suggests involvement of reduced PDH activity in the reduced utilization of glucose in type 1 and type 2 diabetes. On the contrary, hepatic gluconeogenesis is enhanced in type 1 and type 2 diabetes, which also forms one factor causing hyperglycemia. The reduced PDH activity increases pyruvate concentration, which in turn increases availability of lactate as a substrate for hepatic gluconeogenesis. It suggests possible involvement of reduced PDH activity in the enhanced gluconeogenesis in type 1 and type 2 diabetes. When PDH is activated by inhibition of PDHK, the rate of glucose oxidation is considered to rise. As a result, glucose utilization in the body is promoted and hepatic gluconeogenesis is suppressed, whereby hyperglycemia in type 1 and type 2 diabetes is expected to be improved. Another factor contributing to diabetes is impaired insulin secretion, which is known to be associated with reduced PDH activity in pancreatic β cells. It is also known that sustained hyperglycemia due to diabetes causes complications such as neuropathy, retinopathy, nephropathy, cataract and the like. Thiamine and α-lipoic acid contribute to activation of PDH as coenzymes, and also, they or derivatives thereof have been shown to have a promising effect in the treatment of diabetic complications. Thus, activation of PDH is expected to improve diabetic complications.
Under ischemic conditions, limited oxygen supply reduces oxidation of both glucose and fatty acid oxidation and reduces the amount of ATP produced by oxidative phosphorylation in the tissues. In the absence of sufficient oxygen, ATP level is maintained by promoted anaerobic glycolysis. As a result, lactic acid increases and intracellular pH decreases. Even though the body tries to maintain homeostasis of ion by energy consumption, abnormally low ATP level and disrupted cellular osmolarity lead to cell death. In addition, adenosine monophosphate-activating kinase, activated during ischemia, phosphorylates and thus inactivates acetyl-CoA carboxylase. The levels of total malonyl-CoA in the tissue drop, carnitine palmitoyltransferase-I activity is therefore increased and fatty acid oxidation is favored over glucose oxidation by allowing the transport of acyl-CoA into mitochondria. Oxidation of glucose is capable yielding more ATP per mole of oxygen than is oxidation of fatty acids. Under ischemic conditions, therefore, when energy metabolism becomes glucose oxidation dominant by activation of PDH, the ability to maintain ATP level is considered to be enhanced. In addition, since activation of PDH causes oxidation of pyruvate produced by glycolysis, and reducing production of loactate, the net proton burden is considered to be reduced in ischemic tissues. Accordingly, PDH activation by inhibition of PDHK is expected to protectively act in ischemic diseases such as cardiac muscle ischemia.
A drug that activates PDH by inhibition of PDHK is considered to decrease lactate production since it promotes pyruvate metabolism. Hence, such drug is expected to be useful for the treatment of hyperlactacidemia such as mitochondrial disease, mitochondrial encephalomyopathy and sepsis.
In cancer cells, ATP production by oxidative phosphorylation in mitochondria decreases, and ATP production via the anaerobic glycolysis in cytoplasm increases. PDH activation by inhibition of PDHK is expected to promote oxidative phosphorylation in mitochondria, which will induce apoptosis of cancer cells. Therefore, the mechanism is useful for the treatment of cancer diseases. Pulmonary hypertension is characterized by high blood pressure caused by partial narrowing of the pulmonary artery due to promoted cell proliferation therein. In pulmonary hypertension, therefore, activation of PDH in the pulmonary artery cell is expected to promote oxidative phosphorylation in mitochondria, and induce apoptosis of the pulmonary artery cells. Therefore, the mechanism is useful for the treatment of pulmonary hypertension.
It has been shown that dichloroacetic acid, which is a drug having a PDH activating action, provides promising effects for amelioration of hyperglycemia, treatment of myocardial ischemia, treatment of hyperlactacidemia and treatment of cancer diseases. Moreover, usefulness of dichloroacetic acid for the treatment of cerebral ischemia, cerebral apoplexy or pulmonary hypertension has been shown.
From the foregoing findings, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diseases relating to glucose utilization disorder, for example, diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia and hyperlactacidemia. In addition, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.). Furthermore, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diseases caused by limited energy substrate supply to the tissues, for example, cardiac failure, cardiomyopathy, myocardial ischemia, dyslipidemia and atherosclerosis. Additionally, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of cerebral ischemia or cerebral apoplexy. Moreover, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of mitochondrial disease, mitochondrial encephalomyopathy, cancer and the like. Also, it is considered to be useful for the treatment or prophylaxis of pulmonary hypertension.